We have analyzed the mechanism of coupling between receptors and their transduction proteins (guanine nucleotide binding protein, or G proteins) in intact membranes. Classical receptor theory predicts that antagonists passively occupy the binding site of the receptor without altering its conformation, and that receptors are not active in the absence of ligand. We have demonstrated that some opioid and b-adrenergic antagonists act by inducing, upon binding, a state of the receptor which has lesser affinity for the G protein than the unliganded receptor. We have called these ligands "antagonists with negative efficacy", because they disrupt the spontaneous coupling between receptor and G protein in the membrane, and In vivo, may produce effects that are opposite to those of the agonist. We found that receptors can activate G proteins in membranes even in the absence of ligands; this spontaneous interaction is selectively inhibited by sodium ions with a range of concentrations very close to that of the intracellular environment, suggesting that sodium may be a physiological modulator of signals transmitted by G protein-coupled receptors. The spontaneous receptor activity, the effect of sodium, and negative antagonism can all be explained by a ternary-complex model of receptor-G protein interaction, according to which, the association and dissociation of these two molecules in the membrane is governed by a stability constant that is altered upon binding of the ligand. The ability of a ligand to either enhance or diminish this stability constant determines whether such ligand has positive or negative efficacy. Sodium reduces the affinity between receptor and G protein but not the ability of the ligand to perturb their equilibrium. Thus, sodium is an allosteric regulator of signal transduction, which selectively filters hormone-independent "noise" without suppressing hormone-dependent stimuli. We also studied the interaction between multiple receptors stimulating phosphoinositide turnover and activation of protein kinase C in human neuroblastoma cells that are capable of spontaneous interconversion between a neuroblast and glial phenotype. We found that phorbol ester-induced desensitization of receptor-mediated responses exhibits different patterns in the two cell phenotypes, suggesting that protein kinase C regulates molecules involved in signal transduction by distinct mechanisms in the two phenotypes.